This document discusses using 3D molecular similarity and activity cliff analysis to gain insights into structure-activity relationships (SAR). It describes how 3D activity cliffs can be visualized and analyzed in Activity Miner to identify regions causing changes in potency or selectivity. Electrostatic potential differences between molecule pairs can help explain cliffs and drive medicinal chemistry design decisions. Both 2D and 3D similarity are useful for SAR analysis, with 3D providing insights into conformational changes and electrostatic effects influencing activity.

1. Multi-Dimensional Activity Cliff Analysis
Martin slater, Director Consulting

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Finding the critical points in your SAR
Activity Cliffs in 3D from Activity Miner

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Activity Cliffs
> Many names:
> Disparity (Merck 1990s)
> SALI (Guha/Drie 2008)
> Activity Landscapes
> Activity Cliffs
> For each pair of molecules
𝐴𝐴𝑐𝑐𝑐𝑐1 − 𝐴𝐴𝑐𝑐𝑐𝑐2
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎12
> Usually distance = 1 – similarity
> Similarity in 2D
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Where 2D similarity causes problems
> Bioisosteres – low 2D similarity but biologically
similar
> Enantiomers and Chirality
> Locality issues
Fingerprint locality (ECFP4 sim=1.0)
N
N
O
Cl
O
Cl N
N
N
O
O
N
O
O
O
O
N
N
NN
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Using 3D molecular similarity
> 2D metrics are easy: 1:1 map to topology
> 3D is defined for conformers, not for molecules
0.66
0.92
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Context required for 3D similarity
> Need context for 3D similarity – bound to the
protein
> Align all molecules in the active site
> Ligand view of alignment more informative than a
protein view?
N
N
S
N
O
O
N
N
S
N
O
O
N
N
S
N
O
O
N
N
S
N
O
O
N
N
S
N
O
O
Protein ‘view’
of alignment
Ligand ‘view’
of alignment
Signal
N
O
N
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3D disparity in Forge’s Activity Miner
1. Generate conformers
2. Align to reference(s)
3. Calculate similarity matrix on aligned
conformations
> Allow small movements
4. Calculate disparity matrix from similarity
numbers
> Similarity cutoff of 0.95 (Distance cutoff of 0.05)
5. Visualise
> Difficult – 100 molecules gives 4950 pairs!
𝐴𝐴𝑐𝑐𝑐𝑐1 − 𝐴𝐴𝑐𝑐𝑐𝑐2
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎12

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Top Pairs
Highest Disparity Pairs Resort on any column

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Disparity Matrix
Click to cell to send
to 3D window
Molecules
Molecules
Coloured by Disparity
Strong colours  SAR
Sortable table

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Activity View
Ten Nearest
Compounds,
height = distance
Shade = Disparity
Strong colours = Strong SAR
Current Focus
Compound
Comparator compound
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Fields Electrostatic Environment
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Field Differences Inform Decisions
Difference plot – Regions where each molecule has stronger electrostatics
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Detailed Electrostatics decode SAR
Has an effect here
Also has an effect here!
Difference plot – Regions where each molecule has stronger electrostatics
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Selectivity Cliffs
> Selectivity often as important as potency
> Look at what structural changes caused large
changes in selectivity
> Now our visualisation problems are even worse!
𝜅𝜅 ≈
∆ 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆
∆ 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆
=
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝛽𝛽
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝑎𝑎
𝐴𝐴
−
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝛽𝛽
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝑎𝑎
𝐵𝐵
1 − 𝑆𝑆𝑆𝑆 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆
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Visualising Selectivity Cliffs
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Activity View
Red/Green = ↓ pKiβ, ↑ pKiα
→ PI3Kα selective
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Selectivity matrices
Red = ↓ pKiβ
Green = ↑ pKiα
→ more α selective
GDC-0941
pKiα = 9.06
pKiβ= 8.02
6
pKiα = 9.06
pKiβ= 7.02
Sim 0.90
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Why?
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More Electrostatic Differences
> Explain changes in selectivity (how does an
indazole compare to a 2-aminopyrimidine?)
α/β=8.05/8.3 α/β=7.3/5.9
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Conclusions
> Activity Cliff/Disparity analysis provides quick insights
into SAR
> Focus on understanding the reason for a cliff
> Drive design decisions
> Multiple ways to navigate the data
> Compound focus > Most significant changes
> Global overview > Cluster analysis
> 2D and 3D both useful
> 2D provides insights into conformational changes
> 3D provides insights into electrostatic effects
> Visualising multiple activities simultaneously allows
selectivity analysis
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Acknowledgements
> Andy Vinter
> Founder Cresset
> Tim Cheeseright
> Director of products
> Rae Lawrence
> North America sales and support
> Nigel Palmer
> Developer
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> 3D Activity Cliffs available in Activity Miner module for
Forge and Torch
3D Activity Cliffs
3D Design tool, SAR interpretation
SAR interpretation & Activity Cliffs, 3D Design,
3D QSAR, Pharmacophore modeling
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mark@cresset-group.com
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